Relative elevations in tumor cell glutathione (GSH) and GSH biosynthetic enzymes have been strongly associated with drug resistance in ovarian tumor cells both vitro and in vivo. Correspondingly depletion of GSH by buthionine sulfoximine (BSO), an inhibitor of y-glutamylcysteine synthetase (GCS), the rate limiting step in GSH biosynthesis, has reversed drug resistance in these same cells. These data along with the clinical activity observed in heavily pretreated ovarian cancer during phase I studies of BSO and melphalan (L-PAM) strongly suggest that further study of this combination in refractory ovarian cancer is warranted. The primary goal of this project is to assess the clinical effectiveness of GSH modulation (BSO-induced depletion) combined with iv L-PAM through the performance of a phase Il study in refractory ovarian cancer patients with the statistical power to determine if the response rate is greater than 20%. BSO will be administered by a 72-hour continuous infusion which has been observed in our phase I study to consistently deplete tumor GSH to less than 100% of control. Because BSO modulates L-PAM cytotoxicity via inhibition of GCS, the pharmacodynamics effects of BSO administration upon tumor and peripheral lymphocyte GSH levels, GCS activity and mRNA expression will be examined. The second goal is to evaluate GSH levels, GCS activity and mRNA expression of GCS (both heavy and light subunit) in tumor cells before BSO exposure to test for any relationship to clinical outcome with BSO + L-PAM. Data have implied that GCS may be a better predictor of sensitivity to GSH-related chemomodulation than GSH. This is an important issue in cancer-related healthcare since ovarian cancer is a lethal disease which strikes 1 in 70 American women and tumor cell resistance to chemotherapy is a major obstacle in the pursuit of curative therapy for ovarian cancer.
| Anderson, Clarke P; Matthay, Katherine K; Perentesis, John P et al. (2015) Pilot study of intravenous melphalan combined with continuous infusion L-S,R-buthionine sulfoximine for children with recurrent neuroblastoma. Pediatr Blood Cancer 62:1739-46 |
